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Milton Packer - One of the best experts on this subject based on the ideXlab platform.
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angiotensin Neprilysin inhibition in heart failure with preserved ejection fraction
The New England Journal of Medicine, 2019Co-Authors: Scott D Solomon, Milton Packer, John J V Mcmurray, Inder S Anand, Carolyn S P Lam, Aldo P Maggioni, Felipe Martinez, Marc A Pfeffer, Burkert Pieske, Margaret M RedfieldAbstract:Abstract Background The angiotensin receptor–Neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients ...
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b type natriuretic peptide during treatment with sacubitril valsartan the paradigm hf trial
Journal of the American College of Cardiology, 2019Co-Authors: Peder L. Myhre, Brian Claggett, Akshay S. Desai, Milton Packer, Muthiah Vaduganathan, Martin P Lefkowitz, Karl Swedberg, Michael R Zile, John J V McmurrayAbstract:Abstract Background Natriuretic peptides are substrates of Neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with Neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the Neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of Neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-Neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
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effect of Neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin angiotensin system a secondary analysis of the paradigm hf trial
The Lancet Diabetes & Endocrinology, 2018Co-Authors: Milton Packer, Brian Claggett, John J V Mcmurray, Martin P Lefkowitz, Scott D Solomon, Jean L Rouleau, Michael R ZileAbstract:Summary Background Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of Neprilysin inhibition on the course of renal function in patients with type 2 diabetes. Methods In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. Findings eGFR decreased by 1·1 mL/min per 1·73 m 2 per year (95% CI 1·0–1·2) in patients without diabetes, but by 2·0 mL/min per 1·73 m 2 per year (1·9–2·1) in those with diabetes (p vs −1·8 mL/min per 1·73 m 2 per year; p 2 per year [95% CI 0·4–0·8] in patients with vs 0·3 mL/min per 1·73 m 2 per year [0·2–0·5] in those without diabetes; p interaction =0·038). The greater effect of Neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA 1c . The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0·41). Interpretation In patients in whom the renin-angiotensin system is already maximally blocked, the addition of Neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. Funding Novartis.
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derangements in adrenergic adipokine signalling establish a neurohormonal basis for obesity related heart failure with a preserved ejection fraction
European Journal of Heart Failure, 2018Co-Authors: Milton PackerAbstract:Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, Neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta2 -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation. This interplay leads to striking activation of the mineralocorticoid receptor, possibly explaining why obese patients with heart failure are most likely to benefit from spironolactone and eplerenone in large-scale clinical trials. Additionally, adipocytes express and release Neprilysin, which (by degrading endogenous natriuretic peptides) can further promote plasma volume expansion and cardiac fibrosis. Heightened Neprilysin activity may explain the low circulating levels of natriuretic peptides in obesity, the accelerated breakdown of natriuretic peptides in HFpEF, and the cardiac decompression following Neprilysin inhibition in HFpEF patients who are obese. Furthermore, as adipose tissue accumulates and becomes dysfunctional, its secretion of leptin promotes renal sodium retention, microvascular changes and fibrotic processes in the heart, and systemic inflammation; these effects may be mediated or potentiated by the activation of beta2 -adrenergic receptors. These adrenergic-adipokine interactions provide a mechanistic framework for novel therapeutic strategies to alleviate the pathophysiological abnormalities of obesity-related HFpEF. Ongoing trials are well-positioned to test this hypothesis.
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leptin aldosterone Neprilysin axis identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity
Circulation, 2018Co-Authors: Milton PackerAbstract:Obesity (especially visceral adiposity) can be associated with 3 different phenotypes of heart failure: heart failure with a reduced ejection fraction, heart failure with a preserved ejection fraction, and high-output heart failure. All 3 phenotypes are characterized by an excessive secretion of aldosterone and sodium retention. In addition, obesity is accompanied by increased signaling through the leptin receptor, which can promote activation of both the sympathetic nervous system and the renin-angiotensin system and can directly stimulate the secretion of aldosterone. The deleterious interaction of leptin and aldosterone is potentiated by the simultaneous action of adiposity and the renal sympathetic nerves to cause overactivity of Neprilysin; the loss of the counterbalancing effects of natriuretic peptides is exacerbated by an additional effect of both obesity and heart failure to interfere with adiponectin signaling. This intricate neurohormonal interplay leads to plasma volume expansion as well as to adverse ventricular remodeling and cardiac fibrosis. Furthermore, the activity of aldosterone and Neprilysin is not only enhanced by obesity, but these mechanisms can also promote adipogenesis and adipocyte dysfunction, thereby enhancing the positive feedback loop. Last, in elderly obese women, changes in quantity and biology of epicardial adipose tissue further enhances the release of leptin and other proinflammatory adipokines, thereby leading to cardiac and systemic inflammation, end-organ fibrosis, and multiple comorbidities. Regardless of the phenotypic expression, activation of the leptin-aldosterone-Neprilysin axis appears to contribute importantly to the evolution and progression of heart failure in people with obesity. Efforts to interfere with the detrimental interactions of this distinctive neurohormonal ecosystem with existing or novel therapeutic agents are likely to yield unique clinical benefits.
John J V Mcmurray - One of the best experts on this subject based on the ideXlab platform.
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angiotensin Neprilysin inhibition in heart failure with preserved ejection fraction
The New England Journal of Medicine, 2019Co-Authors: Scott D Solomon, Milton Packer, John J V Mcmurray, Inder S Anand, Carolyn S P Lam, Aldo P Maggioni, Felipe Martinez, Marc A Pfeffer, Burkert Pieske, Margaret M RedfieldAbstract:Abstract Background The angiotensin receptor–Neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients ...
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from ace inhibitors arbs to arnis in coronary artery disease and heart failure part 2 5
Journal of the American College of Cardiology, 2019Co-Authors: John J V Mcmurray, Darryl P Leong, Philip Joseph, Salim YusufAbstract:The pharmacological inhibition of the renin-angiotensin-aldosterone system as a therapeutic strategy is one of the most significant advances in the treatment and prevention of cardiovascular disease in heart failure with reduced ejection fraction and in coronary artery disease. Recently, the addition of Neprilysin inhibition to angiotensin receptor blockade has been shown to be even more effective than angiotensin-converting enzyme inhibition alone in heart failure with reduced ejection fraction, marking an important new milestone in heart failure treatment. This review summarizes the major trials that have informed the clinical role of inhibition of the renin-angiotensin-aldosterone and Neprilysin pathways, as well as the limitations of these strategies.
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b type natriuretic peptide during treatment with sacubitril valsartan the paradigm hf trial
Journal of the American College of Cardiology, 2019Co-Authors: Peder L. Myhre, Brian Claggett, Akshay S. Desai, Milton Packer, Muthiah Vaduganathan, Martin P Lefkowitz, Karl Swedberg, Michael R Zile, John J V McmurrayAbstract:Abstract Background Natriuretic peptides are substrates of Neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with Neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the Neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of Neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-Neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
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effect of Neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin angiotensin system a secondary analysis of the paradigm hf trial
The Lancet Diabetes & Endocrinology, 2018Co-Authors: Milton Packer, Brian Claggett, John J V Mcmurray, Martin P Lefkowitz, Scott D Solomon, Jean L Rouleau, Michael R ZileAbstract:Summary Background Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of Neprilysin inhibition on the course of renal function in patients with type 2 diabetes. Methods In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. Findings eGFR decreased by 1·1 mL/min per 1·73 m 2 per year (95% CI 1·0–1·2) in patients without diabetes, but by 2·0 mL/min per 1·73 m 2 per year (1·9–2·1) in those with diabetes (p vs −1·8 mL/min per 1·73 m 2 per year; p 2 per year [95% CI 0·4–0·8] in patients with vs 0·3 mL/min per 1·73 m 2 per year [0·2–0·5] in those without diabetes; p interaction =0·038). The greater effect of Neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA 1c . The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0·41). Interpretation In patients in whom the renin-angiotensin system is already maximally blocked, the addition of Neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. Funding Novartis.
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the angiotensin receptor Neprilysin inhibitor arni sacubitril valsartan improves left ventricular myocardial deformation in heart failure with preserved ejection fraction paramount trial
Journal of the American College of Cardiology, 2018Co-Authors: Tor Bieringsorensen, Brian Claggett, Milton Packer, Burkert Pieske, Michael Zile, Martin Lefkowitz, Adriaan A Voors, Amil M Shah, Elisabeth Pieskekraigher, John J V McmurrayAbstract:The angiotensin receptor Neprilysin inhibitor (ARNI) sacubitril/valsartan (S/V) improves cardiovascular outcomes in heart failure with reduced ejection fraction (HFrEF), and reduced NT-proBNP and left atrial size in a phase II heart failure with preserved ejection fraction (HFpEF) trial. Global
Brian Claggett - One of the best experts on this subject based on the ideXlab platform.
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b type natriuretic peptide during treatment with sacubitril valsartan the paradigm hf trial
Journal of the American College of Cardiology, 2019Co-Authors: Peder L. Myhre, Brian Claggett, Akshay S. Desai, Milton Packer, Muthiah Vaduganathan, Martin P Lefkowitz, Karl Swedberg, Michael R Zile, John J V McmurrayAbstract:Abstract Background Natriuretic peptides are substrates of Neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with Neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the Neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of Neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-Neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
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effect of Neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin angiotensin system a secondary analysis of the paradigm hf trial
The Lancet Diabetes & Endocrinology, 2018Co-Authors: Milton Packer, Brian Claggett, John J V Mcmurray, Martin P Lefkowitz, Scott D Solomon, Jean L Rouleau, Michael R ZileAbstract:Summary Background Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of Neprilysin inhibition on the course of renal function in patients with type 2 diabetes. Methods In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. Findings eGFR decreased by 1·1 mL/min per 1·73 m 2 per year (95% CI 1·0–1·2) in patients without diabetes, but by 2·0 mL/min per 1·73 m 2 per year (1·9–2·1) in those with diabetes (p vs −1·8 mL/min per 1·73 m 2 per year; p 2 per year [95% CI 0·4–0·8] in patients with vs 0·3 mL/min per 1·73 m 2 per year [0·2–0·5] in those without diabetes; p interaction =0·038). The greater effect of Neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA 1c . The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0·41). Interpretation In patients in whom the renin-angiotensin system is already maximally blocked, the addition of Neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. Funding Novartis.
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the angiotensin receptor Neprilysin inhibitor arni sacubitril valsartan improves left ventricular myocardial deformation in heart failure with preserved ejection fraction paramount trial
Journal of the American College of Cardiology, 2018Co-Authors: Tor Bieringsorensen, Brian Claggett, Milton Packer, Burkert Pieske, Michael Zile, Martin Lefkowitz, Adriaan A Voors, Amil M Shah, Elisabeth Pieskekraigher, John J V McmurrayAbstract:The angiotensin receptor Neprilysin inhibitor (ARNI) sacubitril/valsartan (S/V) improves cardiovascular outcomes in heart failure with reduced ejection fraction (HFrEF), and reduced NT-proBNP and left atrial size in a phase II heart failure with preserved ejection fraction (HFpEF) trial. Global
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a cost effectiveness analysis in the us of lcz696 sacubitril valsartan versus renin angiotensin aldosterone system inhibition for heart failure patients with reduced ejection fraction
Journal of the American College of Cardiology, 2016Co-Authors: Thomas A Gaziano, Brian Claggett, Milton Packer, John J V Mcmurray, Karl Swedberg, Jean L Rouleau, Michael Zile, Gregg C Fonarow, Wing Sze Chan, Stuart TurnerAbstract:The angiotensin receptor Neprilysin inhibitor LCZ696 (sacubitril/valsartan) reduced all-cause death and HF hospitalizations compared to enalapril. We assessed the cost-effectiveness of LCZ696 relative to enalapril in the US. Using PARADIGM-HF trial data, a two-state Markov model was developed for
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influence of ejection fraction on outcomes and efficacy of sacubitril valsartan lcz696 in heart failure with reduced ejection fraction the prospective comparison of arni with acei to determine impact on global mortality and morbidity in heart failure paradigm hf trial
Circulation-heart Failure, 2016Co-Authors: Scott D Solomon, Brian Claggett, Akshay S. Desai, Milton Packer, Karl Swedberg, Michael R Zile, Randall C Starling, Jean L Rouleau, Victor Shi, Omer KozanAbstract:Background—The angiotensin receptor Neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and...
Michael R Zile - One of the best experts on this subject based on the ideXlab platform.
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b type natriuretic peptide during treatment with sacubitril valsartan the paradigm hf trial
Journal of the American College of Cardiology, 2019Co-Authors: Peder L. Myhre, Brian Claggett, Akshay S. Desai, Milton Packer, Muthiah Vaduganathan, Martin P Lefkowitz, Karl Swedberg, Michael R Zile, John J V McmurrayAbstract:Abstract Background Natriuretic peptides are substrates of Neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with Neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the Neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of Neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-Neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
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effect of Neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin angiotensin system a secondary analysis of the paradigm hf trial
The Lancet Diabetes & Endocrinology, 2018Co-Authors: Milton Packer, Brian Claggett, John J V Mcmurray, Martin P Lefkowitz, Scott D Solomon, Jean L Rouleau, Michael R ZileAbstract:Summary Background Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of Neprilysin inhibition on the course of renal function in patients with type 2 diabetes. Methods In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. Findings eGFR decreased by 1·1 mL/min per 1·73 m 2 per year (95% CI 1·0–1·2) in patients without diabetes, but by 2·0 mL/min per 1·73 m 2 per year (1·9–2·1) in those with diabetes (p vs −1·8 mL/min per 1·73 m 2 per year; p 2 per year [95% CI 0·4–0·8] in patients with vs 0·3 mL/min per 1·73 m 2 per year [0·2–0·5] in those without diabetes; p interaction =0·038). The greater effect of Neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA 1c . The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0·41). Interpretation In patients in whom the renin-angiotensin system is already maximally blocked, the addition of Neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. Funding Novartis.
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influence of ejection fraction on outcomes and efficacy of sacubitril valsartan lcz696 in heart failure with reduced ejection fraction the prospective comparison of arni with acei to determine impact on global mortality and morbidity in heart failure paradigm hf trial
Circulation-heart Failure, 2016Co-Authors: Scott D Solomon, Brian Claggett, Akshay S. Desai, Milton Packer, Karl Swedberg, Michael R Zile, Randall C Starling, Jean L Rouleau, Victor Shi, Omer KozanAbstract:Background—The angiotensin receptor Neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and...
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elevation in high sensitivity troponin t in heart failure and preserved ejection fraction and influence of treatment with the angiotensin receptor Neprilysin inhibitor lcz696
Circulation-heart Failure, 2014Co-Authors: Pardeep S Jhund, Brian Claggett, Milton Packer, Michael R Zile, Margaret F Prescott, Burkert Pieske, Adriaan A Voors, Elisabeth Kraigherkrainer, Amil M Shah, Victor ShiAbstract:Background—Elevated high-sensitivity troponin is associated with increasing disease severity in patients with stable heart failure with reduced ejection fraction, but less is known about the association in heart failure with preserved ejection fraction. Methods and Results—We examined the prevalence of elevated high-sensitivity troponin T (hs-TnT) in 298 patients with heart failure with preserved ejection fraction enrolled in the Prospective comparison of angiotensin receptor Neprilysin inhibitor with angiotensin receptor blocker on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial, in which the angiotensin receptor Neprilysin inhibitor LCZ696 reduced markers of heart failure severity compared with valsartan. We assessed the association between hs-TnT and cardiac structure and function, and the effect of LCZ696, compared with valsartan, on hs-TnT over 36 weeks. Elevated hs-TnT in the myocardial injury range (>0.014 μg/L) was found in 55% of patients and was associated with old...
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independence of the blood pressure lowering effect and efficacy of the angiotensin receptor Neprilysin inhibitor lcz696 in patients with heart failure with preserved ejection fraction an analysis of the paramount trial
European Journal of Heart Failure, 2014Co-Authors: Pardeep S Jhund, Brian Claggett, Milton Packer, Martin P Lefkowitz, Michael R Zile, Victor Shi, Burkert Pieske, Adriaan A Voors, Toni Bransford, John J V McmurrayAbstract:AimsThe first in class angiotensin receptor Neprilysin inhibitor, LCZ696 has been shown to reduce levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), reduce left atrial size and improve New York Heart Association (NYHA) class in patients with heart failure with preserved ejection fraction (HFpEF). We examined whether the effects of LCZ696 were independent of systolic blood pressure (SBP) lowering. Methods and resultsIn the Prospective comparison of ARNi (angiotensin receptor Neprilysin inhibitor) with ARB (angiotensin receptor blocker) on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial 301 patients were randomly assigned to LCZ696 or valsartan. We examined the relationship between SBP lowering and LCZ696 on NT-proBNP level, left atrial size, NYHA class and estimated glomerular filtration rate (eGFR). By 12weeks blood pressure was reduced by 9mmHg (SD 15)/5mmHg (SD 11) in patients receiving LCZ696 in comparison with 3mmHg (SD 17)/2mmHg (SD 12) in those receiving valsartan. The change in NT-proBNP was poorly correlated with change in SBP (LCZ696, r=0.17, P=0.06; valsartan, r=0.05, P=0.58) After adjustment for change in SBP, the ratio of change in NT-proBNP at 12weeks for LCZ696 vs. valsartan was 0.76 (95% CI 0.63-0.93, P=0.008), and similar to the ratio not adjusting for SBP (0.76, 95% CI 0.63-0.92, P=0.006); P for interaction was 0.38). Similarly, reduction in left atrial volume index at 36weeks, improvement in NYHA class and eGFR were all independent of the change in SBP. ConclusionIn patients with HFpEF, the effect of the angiotensin receptor Neprilysin inhibitor LCZ696 on NT-proBNP, left atrial volume, functional class, and eGFR was independent of reduction in SBP.
Scott D Solomon - One of the best experts on this subject based on the ideXlab platform.
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angiotensin Neprilysin inhibition in heart failure with preserved ejection fraction
The New England Journal of Medicine, 2019Co-Authors: Scott D Solomon, Milton Packer, John J V Mcmurray, Inder S Anand, Carolyn S P Lam, Aldo P Maggioni, Felipe Martinez, Marc A Pfeffer, Burkert Pieske, Margaret M RedfieldAbstract:Abstract Background The angiotensin receptor–Neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients ...
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effect of Neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin angiotensin system a secondary analysis of the paradigm hf trial
The Lancet Diabetes & Endocrinology, 2018Co-Authors: Milton Packer, Brian Claggett, John J V Mcmurray, Martin P Lefkowitz, Scott D Solomon, Jean L Rouleau, Michael R ZileAbstract:Summary Background Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of Neprilysin inhibition on the course of renal function in patients with type 2 diabetes. Methods In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. Findings eGFR decreased by 1·1 mL/min per 1·73 m 2 per year (95% CI 1·0–1·2) in patients without diabetes, but by 2·0 mL/min per 1·73 m 2 per year (1·9–2·1) in those with diabetes (p vs −1·8 mL/min per 1·73 m 2 per year; p 2 per year [95% CI 0·4–0·8] in patients with vs 0·3 mL/min per 1·73 m 2 per year [0·2–0·5] in those without diabetes; p interaction =0·038). The greater effect of Neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA 1c . The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0·41). Interpretation In patients in whom the renin-angiotensin system is already maximally blocked, the addition of Neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. Funding Novartis.
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influence of ejection fraction on outcomes and efficacy of sacubitril valsartan lcz696 in heart failure with reduced ejection fraction the prospective comparison of arni with acei to determine impact on global mortality and morbidity in heart failure paradigm hf trial
Circulation-heart Failure, 2016Co-Authors: Scott D Solomon, Brian Claggett, Akshay S. Desai, Milton Packer, Karl Swedberg, Michael R Zile, Randall C Starling, Jean L Rouleau, Victor Shi, Omer KozanAbstract:Background—The angiotensin receptor Neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and...
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combined Neprilysin and renin angiotensin system inhibition for the treatment of heart failure
Jacc-Heart Failure, 2014Co-Authors: Orly Vardeny, Ryan M Miller, Scott D SolomonAbstract:Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds. Inhibiting Neprilysin has been a therapeutic target for several compounds that have been tested in cardiovascular disease, including ecadotril, candoxatril, omapatrilat, and LCZ696. Although ecadotril, candoxatril, and omapatrilat were initially tested in hypertension and/or heart failure, lack of efficacy and side effects led to discontinuation of their development. LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor Neprilysin inhibitor that has been developed for use in heart failure. This compound is composed of 2 molecular moieties in a single crystalline complex-the angiotensin receptor blocker valsartan and a Neprilysin inhibitor prodrug-and has now been tested in hypertension, in a phase 2 trial in heart failure with preserved ejection fraction, and has demonstrated greater efficacy than enalapril in a phase 3 trial in heart failure with reduced ejection fraction. Its ability to inhibit the renin-angiotensin-aldosterone axis and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.
